Right Ventricular Strain Improves the Echocardiographic Diagnosis and Risk Stratification of Transthyretin Cardiac Amyloidosis Among Other Phenotypes of Left Ventricular Hypertrophy.

AIMS: Cardiac amyloidosis is a diffuse disease affecting all cardiac chambers. The value of right ventricular free-wall strain is uncertain as an echocardiographic red flag. We hypothesized that right ventricular free-wall strain is of added value for diagnostic and prognostic purposes in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHOD: A diagnosis of ATTR-CA required positive Tc-99m pyrophosphate scintigraphy and negative serum clonal dyscrasia. Patients with left ventricular (LV) hypertrophy (LVH; interventricular septal thickness ≥1.2 cm) by echocardiography and negative pyrophosphate scintigraphy served as controls after exclusion of amyloid light-chain cardiac amyloidosis. Longitudinal strain was computed with speckle-tracking echocardiography. RESULTS: We studied 108 subjects with ATTR-CA and 106 controls with LVH, retrospectively. Right ventricular free-wall strain was independently associated with the diagnosis of ATTR-CA after adjusting for classical echocardiographic parameters, namely, relative apical sparing (RAS), e', and E/e'. Right ventricular free-wall strain ≥ -16% was incremental to LV RAS in the overall group and in the subgroup without extreme wall thickness (≤1.4 cm; Harrell's C, net reclassification improvement = 0.213, P < .001; and net reclassification improvement = 0.463, P = .015, respectively). Major adverse cardiovascular and cerebrovascular events (heart failure hospitalization, stroke, death) occurred in 47 ATTR-CA patients, during follow-up (median, 38; range, 6-60 months). Right ventricular free-wall strain ≥-16% was associated with 3-fold increased risk of MACCE in ATTR-CA patients independently of age, comorbidities, B-type natriuretic peptide, and tafamidis treatment. Right ventricular free-wall strain was additive to LV ejection fraction for risk stratification (chi square = 10.2; P = .017). CONCLUSIONS: Right ventricular free-wall strain >-16% has incremental value to LV RAS for the differential diagnosis of ATTR-CA among LVH phenotypes and is associated with poor prognosis.

Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

Immune Markers, Blood Pressure Severity, and Cardiac Remodeling 1 to 2 Years After Hypertensive Disorders of Pregnancy.

Background Cardiovascular dysfunction and hypertension can persist postpartum following hypertensive disorders of pregnancy (HDPs). This study hypothesized that activin A, proinflammatory markers and concentric remodeling by echo would be higher 1-2 years postpartum following HDP with persistent hypertension compared to HDP with normalized blood pressure (BP). We further hypothesized correlations between biomarkers with BP and echocardiographic indices. Methods and Results This study enrolled participants with HDPs but no prepregnancy hypertension followed 1 to 2 years after delivery. Activin A and inflammatory cytokines, BP, and echocardiograms were obtained. Biomarker concentrations and echocardiographic parameters were compared between HDP with and without persistent hypertension. Individuals with persistent hypertension at a mean of 1.6 years postpartum had significantly higher activin A concentrations (median[interquartile range 25-75] 230.6 [196.0-260.9] versus 175.3 pg/mL [164.3-188.4]; P<0.01), more concentric left ventricular concentric remodeling (relative wall thickness >0.42, 48% versus 7%; P<0.01), and worse peak left atrial strain (33.4% versus 39.3%; P<0.05) as compared with those whose BP normalized. Higher activin A and interleukin-6 concentrations correlated with higher systolic (activin A: r=0.43, P=0.01) and diastolic BP (activin A: r=0.58, P<0.01; interleukin-6: r=0.36; P<0.05), as well as greater left ventricular thickness (activin A and interventricular septal thickness: r=0.41, interleukin-6 and interventricular septal thickness: r=0.36; both P<0.05). Conclusions Individuals with HDPs and persistent hypertension had significantly higher activin A and greater concentric remodeling compared with those with HDPs and normalized BP at 1 to 2 years postpartum. Activin A was positively correlated with both BP and echocardiographic indices (left ventricular thickness), suggesting overlapping processes between persistent hypertension and cardiac remodeling.

Cardiovascular outcomes in breast cancer survivors: a systematic review and meta-analysis.

AIMS: It is unclear whether the future risk of cardiovascular events in breast cancer (Bc) survivors is greater than in the general population. This meta-analysis quantifies the risk of cardiovascular disease development in Bc patients, compared to the risk in a general matched cancer-free population, and reports the incidence of cardiovascular events in patients with Bc. METHODS AND RESULTS: We searched PubMed, Scopus, and Web of Science databases (up to 23 March 2022) for observational studies and post hoc analyses of randomized controlled trials. Cardiovascular death, heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), and stroke were the individual endpoints for our meta-analysis. We pooled incidence rates (IRs) and risk in hazard ratios (HRs), using random-effects meta-analyses. Heterogeneity was reported through the I2 statistic, and publication bias was examined using funnel plots and Egger's test in the meta-analysis of risk. One hundred and forty-two studies were identified in total, 26 (836 301 patients) relevant to the relative risk and 116 (2 111 882 patients) relevant to IRs. Compared to matched cancer-free controls, Bc patients had higher risk for cardiovascular death within 5 years of cancer diagnosis [HR = 1.09; 95% confidence interval (CI): 1.07, 1.11], HF within 10 years (HR = 1.21; 95% CI: 1.1, 1.33), and AF within 3 years (HR = 1.13; 95% CI: 1.05, 1.21). The pooled IR for cardiovascular death was 1.73 (95% CI 1.18, 2.53), 4.44 (95% CI 3.33, 5.92) for HF, 4.29 (95% CI 3.09, 5.94) for CAD, 1.98 (95% CI 1.24, 3.16) for MI, 4.33 (95% CI 2.97, 6.30) for stroke of any type, and 2.64 (95% CI 2.97, 6.30) for ischaemic stroke. CONCLUSION: Breast cancer exposure was associated with the increased risk for cardiovascular death, HF, and AF. The pooled incidence for cardiovascular endpoints varied depending on population characteristics and endpoint studied. REGISTRATION: CRD42022298741.

This work investigated the absolute and relative risk of cardiovascular outcomes in breast cancer survivors. Breast cancer was associated with a higher risk of cardiovascular death, heart failure (HF), and atrial fibrillation when compared to the general population.The incidence for cardiovascular death, HF, and coronary artery disease were 1.73, 4.44, and 4.29 per 1000 person-years, respectively.Clinicians should carefully assess breast cancer survivors for their cardiovascular risk factor profile and monitor their cardiovascular function.

Primary Carnitine Deficiency as a Treatable Cause of Heart Failure in Young Patients.

Non-ischemic dilated cardiomyopathy is the most common subgroup of heart failure in young adults. Several metabolic defects could be the underlying etiology in these young heart failure patients. However, most cases are considered idiopathic. Primary carnitine deficiency is an overlooked inherited metabolic disease causing cardiomyopathy in these patients. Oral carnitine replacement therapy could prevent primary carnitine deficiency patients from progressing to advanced heart failure and life-threatening arrhythmias. In this case report, we present an index primary carnitine deficiency case and his brother's diagnosis and successful treatment period to draw attention to primary carnitine deficiency as a treatable cause of heart failure in young adults.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

The Safety and Tolerability of Nebivolol in Hypertensive Patients with Coronary Artery Disease and Left Ventricular Ejection Fraction ≥ 40%: A Population-Based Cohort Study (Nebivolol-TR Study).

BACKGROUND: This study aimed to assess the safety and tolerability of nebivolol in hypertensive patients with coronary artery disease and left ventricular ejection fraction ≥ 40% in a Turkish cohort. METHODS: A total of 1015 hypertensive patients and coronary artery disease with left ventricular ejection fraction ≥ 40% were analyzed from 29 different centers in Turkey. Primary outcomes were the mean change in blood pressure and heart rate. Secondary outcomes were to assess the rate of reaching targeted blood pressure (<130/80 mmHg) and heart rate (<60 bpm) and the changes in the clinical symptoms (angina and dyspnea). Adverse clinical events and clinical outcomes including cardiovascular mortality, cardiovascular hospital admissions, or acute cardiac event were recorded. RESULTS: The mean age of the study population was 60.3 ± 11.5 years (male: 54.2%). During a mean follow-up of 6 months, the mean change in blood pressure was -11.2 ± 23.5/-5.1 ± 13.5 mmHg, and the resting heart rate was -12.1 ± 3.5 bpm. Target blood pressure and heart rate were achieved in 76.5% and 37.7% of patients. Angina and functional classifications were improved by at least 1 or more categories in 31% and 23.2% of patients. No serious adverse events related to nebivolol were reported. The most common cardiovascular side effect was symptomatic hypotension (4.2%). The discontinuation rate was 1.7%. Cardiovascular hospital admission rate was 5% and hospitalization due to heart failure was 1.9% during 6 months' follow-up. Cardiovascular mortality rate was 0.1%. CONCLUSION: Nebivolol was well tolerated and safe for achieving blood pressure and heart rate control in hypertensive patients with coronary artery disease and heart failure with preserved or mildly reduced ejection fraction.

Takotsubo syndrome early after treatment due to non cardiotoxic chemotherapy agents.

Takotsubo syndrome (TTS), acute stress-induced cardiomyopathy, is known to have a dramatic clinical presentation mimicking acute myocardial infarction. Recently developed chemotherapeutic drugs have resulted in improvements in morbidity and mortality in many forms of cancer. However, some chemotherapeutic drugs are cardiotoxic and may cause heart failure. Gemcitabine and vinorelbine are commonly used drugs for various solid organ neoplasms. While neither of these chemotherapeutic drugs has been directly associated with cardiotoxicity, there are a few case reports in the literature related to gemcitabine treatment- induced cardiomyopathy. This case report describes a case of TTS developing within hours of gemcitabine and vinorelbine chemotherapy.

Prevalence of inappropriate sinus tachycardia and the comparison of the heart rate variability characteristics with propensity score-matched controls.

OBJECTIVE: Inappropriate sinus tachycardia (IST) is a syndrome characterized by an elevated resting heart rate with distressing symptoms and no secondary cause of sinus tachycardia. This study was conducted to evaluate both the prevalence of IST among symptomatic patients and heart rate variability (HRV) characteristics. METHODS: The records of all consecutive symptomatic patients who had undergone 24-hour Holter monitoring between September 2015 and November 2016 at a single center were retrospectively evaluated. IST was defined as a 24-hour mean heart rate (HR) of ≥90 beats/minute and a resting HR of ≥100 beats/minute in the absence of any secondary cause of sinus tachycardia. All of the study data related to clinical characteristics, symptoms, concomitant diseases, and Holter electrocardiogram parameters were obtained from the electronic hospital records. A propensity age- and sex-matched control group was selected from a non-IST patient cohort. RESULTS: A total of 1865 consecutive patients were evaluated and 32% were excluded due to an inadequate Holter recording period or insufficient quality, atrial fibrillation episodes, atrioventricular block, or >1% atrial or ventricular extrasystoles. Among 1265 patients with sinus rhythm, 4.98% (n=63) had IST. The IST patients were younger (39.6±17.4 vs. 50.2±17.2 years; <0.001), and female gender was more prominent (60.3% vs. 43.8%; p=0.009). All of the time and frequency domain parameters of HRV except the low frequency/high frequency ratio were significantly reduced in the IST group compared with the propensity-matched controls. CONCLUSION: The IST prevalence among symptomatic patients in sinus rhythm was 4.98%. IST was primarily seen in younger women, and they had diminished time and frequency domain HRV parameters.

The real-life data of hospitalized patients with heart failure: On behalf of the Journey HF-TR study investigators.

OBJECTIVE: Acute heart failure (AHF) is a life-threatening clinical syndrome characterized by rapid onset of heart failure (HF) symptoms and signs and requires urgent therapy. The aim of the present study was to evaluate the overall clinical characteristics, management, and in-hospital outcomes of hospitalized patients with AHF in a large sample of Turkish population. METHODS: The Journey HF-TR study is a cross-sectional, multicenter, non-invasive and observational trial. Patients who were hospitalized with a diagnosis of AHF in the intensive care unit (ICU)/coronary care unit and cardiology wards between September 2015 and September 2016 were included in our study. RESULTS: A total of 1606 (male: 57.2%, mean age: 67.8±13 years) patients who were diagnosed with AHF were enrolled in the study. Seventeen percent of the patients were admitted to the hospital with a diagnosis of new onset AHF. Hypertension (67%) and coronary artery disease (CAD) (59.6%) were the most frequent underlying diseases. Acute coronary syndrome accompanying HF (14.7%), infection (29.3%), arrhythmia (25.1%), renal dysfunction (23%), and non-compliance with medication (23.8%) were the precipitating factors. The median length of stay in the ICU was 3 days (interquartile range, IQR 1-72) and 7 days (IQR 1-72) for in-hospital journey. The guideline recommended medications were less likely used in our patient population (<73%) before admission and were similar to European and US registers at discharge. The in-hospital mortality rate was 7.6%. Hypertension and CAD were the most frequent underlying diseases in our population similar to other European surveys. Although our study population was younger than other registers, in-hospital mortality was high. CONCLUSION: Analyses of such real-world data will help to prepare a national database and distinctive diagnosis and treatment algorithms and to provide observing compliance with the current European Society of Cardiology guidelines for more effective management of HF.

Is neuropathic pain associated with cardiac sympathovagal activity changes in patients with breast cancer?

Objective Heart rate variability (HRV) is a good indicator of the autonomic nervous system (ANS) activity. A few studies have been conducted recently and have shown a relationship between reduced HRV and conditions that lead to neuropathic pain (NP). In this study, we aimed to investigate whether NP is associated with changes in cardiac sympathovagal activity in patients with breast cancer (BC). Methods We used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire to evaluate NP in 70 patients with BC. The patients were subjected to a 24-h Holter ECG monitorization to determine heart rate variability (HRV). Standard deviation (SD) of the normal-to-normal RR intervals (SDNN), SD of the mean of the RR intervals (SDAAN), mean of the SD of the NN interval (SDNN Index), low-frequency component/high-frequency component ratio (LF/HF), and the mean heart rate of the patients were recorded. Results According to the LANSS questionnaire, 18 (25.7%) of the patients were classified as NP (+). The SDNN (P = 0.001), SDAAN (P = 0.003), and SDDN index (P = 0.007) were significantly lower in patients with NP than in patients without NP, whereas LF/HF ratio (P = 0.000) and mean heart rate were found to be significantly higher in patients with NP (P = 0.006). Conclusion According to our findings, NP (+) patients with BC had increased cardiac sympathetic activity, which was suggested to be associated with increased cardiovascular morbidity and mortality.